Cannabinoid CB1 receptor agonists have been shown to have many therapeutic uses such as neuroprotection, analgesia and appetite stimulation. Cannabinoid antagonists have been shown to be effective against obesity and metabolic syndrome. Despite these and many other therapeutic uses for cannabinoids, FDA approval of cannabinoid drugs has been hampered because agonists produce psychoactivity and dependence and antagonists produce depression and possibly suicidal ideation. There have been thousands of cannabinoid compounds synthesized that targeted the CB1 orthosteric binding pocket, with no success at elimination of untoward effects. We propose here a multidisciplinary approach to overcome the issues with CB1 orthosteric pocket-targeted drugs via the development of functionally selective cannabinoids that target accessory/non-traditional ligand binding sites that are topographically distinct from orthosteric sites or by focusing on allosteric sites at which allosteric modulators themselves are selective in what signal they modulate. The research plan is based upon novel lead compounds that have emerged during the current funding period from computational studies of the CB1 receptor and our close collaborative studies with experimental medicinal chemists, molecular biologists and pharmacologists.